ABSTRACT

Higher educational attainment (EA) is known to have a protective effect regarding the severity of schizophrenia (SZ). However, recent studies have found a small positive genetic correlation between EA and SZ. Here, we investigate possible causes of this counterintuitive finding using genome-wide association results for EA and SZ (n = 443,581) and a replication cohort (1,169 controls and 1,067 cases) with high-quality SZ phenotypes. We find strong genetic overlap between EA and SZ that cannot be explained by chance, linkage disequilibrium, or assortative mating. Instead, our results suggest that the current clinical diagnosis of SZ comprises at least two disease subtypes with non-identical symptoms and genetic architectures: One part resembles bipolar disorder (BIP) and high intelligence, while the other part is a cognitive disorder that is independent of BIP.

Footnotes

↵a The actual N per SNP was not provided in the SZ GWAS summary statistics.

↵b It is typically assumed that GWAS data for European populations contain ≈1,000,000 independent loci. However, the quality-control procedures for GWAS summary statistics in studies like ours decreases the number of independent loci to <1,000,00041,62. In fact, clumping the post-QC GWAS results for SZ without a P value threshold, an R2LD<0.1, and a LD-window of 1,000,000 kb with the 1000 Genomes phase 1 version 3 European reference panel42 leads to only 223,065 independent loci. Thus, assuming 500,000 independent loci in these calculations is conservative.

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